Breast cancer can be treated and prevented by interrupting the function of key growth regulatory receptors. There is a large body of evidence showing that the insulin-like growth factors (IGFs) stimulate several phenotypes characteristic of the malignant breast cancer cell including proliferation, protection from apoptosis, and metastasis. IGF action is potentially mediated by several distinct cell surface receptors. Unlike some growth factor receptors implicated in breast cancer biology, the IGF receptors require interaction with their ligands in order to transmit a relevant biological signal. Thus, the goal of this project is to neutralize IGF action as a method to inhibit breast cancer growth. We hypothesize that inhibition of IGF action by insulin-like growth factor binding protein-1 (IGFBP-1) will be an effective anti-tumor strategy and synergize with other anti-breast cancer strategies. We also will examine if the integrin binding sequence (RGD) contained in IGFBP-1 contributes to its anti-tumor effects. Our specific aims are to: 1) manipulate the pharmacologic properties of IGFBP-1 to maximize its therapeutic effect; 2) use IGFBP-1 to inhibit breast cancer growth in xenograft and transgenic mouse models of breast cancer; 3) combine IGFBP-1 with cytotoxic chemotherapy to enhance breast cancer tumor inhibition; and 4) determine if the integrin binding protein (RGD) motif contained in IGFBP-1 is required for its anti-tumor effects. Our long-term goal is to prove that the IGFs are key targets for the treatment of breast cancer. By optimizing IGF neutralization strategies, we will be prepared to move this anti-IGF strategy into the clinic.